Vedolizumab

12.1 Mechanism of Action Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Vedolizumab does not bind to or inhibit function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1). The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn's disease.

1 INDICATIONS AND USAGE ENTYVIO is indicated in adults for the treatment of: moderately to severely active ulcerative colitis (UC). moderately to severely active Crohn's disease (CD). ENTYVIO is an integrin receptor antagonist indicated in adults for the treatment of: moderately to severely active ulcerative colitis (UC). ( 1 ) moderately to severely active Crohn's disease (CD). ( 1 )

2 DOSAGE AND ADMINISTRATION Important Administration Information Before initiating ENTYVIO, update immunizations according to current immunization guidelines. ( 2.1 , 5.5 ) Intravenous Administration : ENTYVIO should be administered intravenously by a healthcare provider. ( 2.1 ) Subcutaneous Injection : ENTYVIO prefilled syringe and ENTYVIO PEN are intended for subcutaneous use. A patient may self-inject or caregiver may inject after proper training on correct subcutaneous injection technique. ( 2.1 ) Recommended Dosage ( 2.2 ) Week 0 : 300 mg infused intravenously over approximately 30 minutes. Week 2 : 300 mg infused intravenously over approximately 30 minutes. Week 6 : Patients may remain on ENTYVIO intravenous therapy or switch to subcutaneous injection after receiving two ENTYVIO intravenous doses administered at Week 0 and Week 2. Intravenous Infusion : 300 mg infused over approximately 30 minutes and then every eight weeks thereafter. Subcutaneous Injection : 108 mg subcutaneously once every two weeks. Discontinue ENTYVIO in patients who do not show evidence of therapeutic benefit by Week 14. Patients currently receiving and responding to ENTYVIO intravenous therapy after Week 6 may also be switched to subcutaneous injection. Administer the first subcutaneous dose in place of the next scheduled intravenous infusion and every two weeks thereafter. Preparation and Administration Instructions: See full prescribing information for complete information on reconstitution, dilution, administration, and storage. ( 2.3 , 2.4 ) 2.1 Important Administration Information Before initiating ENTYVIO, update immunizations according to current immunization guidelines [see Warnings and Precautions (5.5) ]. Intravenous Administration ENTYVIO should be administered by a healthcare provider prepared to manage hypersensitivity reactions including anaphylaxis, if they occur [see Warnings and Precautions (5.1) ] . Appropriate monitoring and medical support measures should be available for immediate use. Observe patients during infusion and until the infusion is complete. Reconstitute and dilute ENTYVIO lyophilized powder prior to administration as a 30-minute intravenous infusion [see Dosage and Administration (2.3) ]. Subcutaneous Injection ENTYVIO prefilled syringe and ENTYVIO PEN are intended for subcutaneous use under the guidance and supervision of a healthcare professional. Patients may self-inject or caregivers may inject subcutaneous ENTYVIO using either the ENTYVIO prefilled syringe or ENTYVIO PEN after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of ENTYVIO. 2.2 Recommended Dosage in Adults with Ulcerative Colitis and Crohn’s Disease Week 0: Administer ENTYVIO 300 mg by intravenous infusion over approximately 30 minutes [ see Dosage and Administration (2.3) ]. Week 2: Administer ENTYVIO 300 mg by intravenous infusion over approximately 30 minutes. Week 6: Patients may remain on ENTYVIO intravenous therapy or switch to subcutaneous injection after receiving two ENTYVIO intravenous doses administered at Week 0 and Week 2. Intravenous Infusion : Administer ENTYVIO 300 mg by intravenous infusion over approximately 30 minutes and then every eight weeks thereafter. Subcutaneous Injection : Administer ENTYVIO 108 mg subcutaneously once every 2 weeks. Discontinue therapy in patients who show no evidence of therapeutic benefit by Week 14. Patients currently receiving and responding to ENTYVIO intravenous therapy after Week 6 may also be switched to subcutaneous injection. Administer the first subcutaneous dose in place of the next scheduled intravenous infusion and every two weeks thereafter. 2.3 Preparation and Administration Instructions for Intravenous Infusion Reconstitution Instructions Remove the flip-off cap from the single-dose vial and wipe with alcohol swab. Reconstitute ENTYVIO vial containing lyophilized powder with 4.8 mL of Sterile Water for injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection, at room temperature (20°C to 25°C [68ºF to 77ºF]), using a syringe with a 21- to 25-gauge needle. Insert the syringe needle into the vial through the center of the stopper and direct the stream of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection, to the glass wall of the vial to avoid excessive foaming. Gently swirl the vial for at least 15 seconds to dissolve the lyophilized powder. Do not vigorously shake or invert. Allow the solution to sit for up to 20 minutes at room temperature to allow for reconstitution and for any foam to settle; the vial can be swirled and inspected for dissolution during this time. If not fully dissolved after 20 minutes, allow another 10 minutes for dissolution. Do not use the vial if the drug product is not dissolved within 30 minutes. Visually inspect the reconstituted ENTYVIO solution for particulate matter and discoloration prior

6 ADVERSE REACTIONS The following topics are also discussed in detail in the Warnings and Precautions section: Infusion-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3) ] Liver Injury [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo) are: nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities. ( 6.1 ) Adverse reactions with subcutaneous ENTYVIO are similar to those reported with intravenous ENTYVIO with the exception of injection site reactions reported with subcutaneous ENTYVIO. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to intravenous ENTYVIO in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years. Intravenous Infusion The safety data described in Table 2 are derived from four controlled Phase 3 trials (UC Trials I and II and CD Trials I and III); data from adult patients receiving open-label intravenous ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included [see Clinical Studies (14.1 , 14.2) ] . In these trials, 1,434 patients received ENTYVIO 300 mg intravenously for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn's disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III). Adverse reactions were reported in 52% of patients treated with intravenous ENTYVIO and 45% of patients treated with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD Trials I and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with intravenous ENTYVIO compared to 4% of patients treated with placebo (UC Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with ENTYVIO and 9% with placebo). The most common adverse reactions (reported by ≥3% of patients treated with intravenous ENTYVIO in the UC Trials I and II and CD Trials I and III combined group and ≥1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities (Table 2) . Table 2. Adverse Reactions in ≥3% of Intravenous ENTYVIO-Treated Adult Patients and ≥1% Higher than in Placebo (UC Trials I and II Data from patients receiving open-label intravenous ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included. and CD Trials I and III ) Adverse Reaction ENTYVIO IV Patients who received ENTYVIO for up to 52 weeks. (N=1434) Placebo Patients who received placebo for up to 52 weeks. (N=297) Nasopharyngitis 13% 7% Headache 12% 11% Arthralgia 12% 10% Nausea 9% 8% Pyrexia 9% 7% Upper respiratory tract infection 7% 6% Fatigue 6% 3% Cough 5% 3% Bronchitis 4% 3% Influenza 4% 2% Back pain 4% 3% Rash 3% 2% Pruritus 3% 1% Sinusitis 3% 1% Oropharyngeal pain 3% 1% Pain in extremities 3% 1% Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received intravenous ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10-week Crohn's disease trial, are similar to those listed in Table 2 . Infusion-Related Reactions and Hypersensitivity Reactions Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following intravenous ENTYVIO administration in clinical trials [see Warnings and Precautions (5.1) ] . In UC Trials I and II and CD Trials I and III, one case of anaphylaxis [one out of 1,434 patients treated with intravenous ENTYVIO (0.07%)] was reported by a Crohn's disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and

7 DRUG INTERACTIONS 7.1 Natalizumab Products Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab products. 7.2 TNF Blockers Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers. 7.3 CYP450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of certain cytokines (e.g., IL-6, IL-10, TNFα, IFN) during chronic inflammation. Therefore, use of ENTYVIO may normalize the formation of CYP450 enzymes by modulating the underlying disease. Upon initiation or discontinuation of ENTYVIO in patients treated with CYP450 substrates, monitor drug concentrations or other therapeutic parameters, and adjust the dosage of the CYP substrate as needed. See the prescribing information of specific CYP substrates.